Cholinoceptor antagonists Flashcards
Define affinity
The strength with which an agonist binds to a receptor
Both agonists and antagonists will have affinity for the receptor
Define efficacy
Once the drug has bound to the receptor, the ability of the drug to transduce a response and activate intracellular signalling pathways is its efficacy
Only agonists possess efficacy
Where are nicotinic receptors found
In ALL autonomic ganglia- even before adrenal gland
At neuromuscular junctions
Where are muscarinic receptors found
At parasympathetic effector organs and on sweat glands
What are the few clinically useful nicotinic receptor antagonists called and how do they block the receptor?
Ganglion Blocking drugs
These block the ion channel itself, thus preventing the ions from moving through the pore (it doesn’t block the receptor but the channel itself)
Give two examples of ganglion blocking drugs.
Hexamethonium- better at blocking the channel- use as anti-hypertensive obsolete
Trimethaphan- better at blocking the ACh receptor- short-lived- preferred use
Why is the term cholinoceptor antagonist not technically correct
GBDs can act to both antagonise the receptor AND/OR physically block the ion-channel itself.
Classical antagonism is where the receptor is physically blocked- therefore blocking the ion channel doesn’t technically agree with this definition
Do cholinoceptor antagonists have affinity
it depends
if they block the receptor- yes
if they block the ion channel- no
What does the term ‘use-dependant’ block mean
The drugs work most effectively when the ion channels are open.
This means that the more agonist is present at the receptor, the opportunity the antagonist has to block the channel, thus the more useful and effective the drugs can be
i.e when the ion channel is more active- are likely to be open- allowing the drug to enter the channel and physically block it
In classical antagonism, if we have more ACh, is the antagonist more effective
No
Opposite to use-dependant effect for ion channel blockers
Agonist (ACh) would simply outcompete the antagonist
What does the term ‘incomplete block’ mean
Incomplete blocking – Ion-channel blockade is only partial (as some ions still pass through).
due to the use-dependence of the block, the drugs do not completely block the channels, reducing function significantly but not completely
What determines the effect of ganglion blockade in a tissue?
It depends on which limb of the autonomic nervous system predominates in the particular tissue (at the time e.g. at rest)
PSNS innervation n on the heart and lungs is dominant at rest
So GBD would inhibit the PSNS effects on these tissues at rest
Which tissues are sympathetic dominated
Vasculature and kidneys
Liver and adipose to (reduced glycogenolysis, gluconeogensis, and reduced lipolysis)
Describe the differing effects of the SNS on the vasculature
Blood vessels in skeletal muscle- dilatation
Blood vessels in skin, mucous membrane and splanchnic area- constriction
Which of the following effects would
be observed at rest after treatment
with a ganglion blocking drug?
PSNS is dominant at rest
therefore will inhibit PSNS effects
would see bronchodilation and increased heart rate
Which tissues are parasympathetic dominated
Lungs – causes bronchoconstriction
Eyes – maintains partial pupillary constriction at rest
Bladder, ureters and GI tract
Exocrine functions
What is the effect of a GBD on the PSNS dominated tissues at rest
Bronchodilation Pupil dilation (blurred vision) Bladder dysfunction Loss of GI motility and secretions and tone Decrease in exocrine secretion
Describe the CVS effects of GBDs
CVS effects; hypotension – blood vessel vasoconstriction inhibited ( so vasodilation) and kidney renin secretion inhibited (so no AngII).
Fluids are lost
Describe the smooth muscle effects of GBDs
Smooth muscle effects; pupil dilation, decreased GI-tone, bladder dysfunction, bronchodilation.
Describe the effect of GBDs on exocrine secretions
Decreased exocrine secretions
What is hexamethonium
the first anti-hypertensive drug used but LOTS of side effects as very general.
o Primarily an ion-channel blocker (so not a lot of affinity).
Side effects include loss of bladder control
What is trimetephan
very potent ganglion blocking drug used to produce controlled peri-operative hypotension for short duration (blocks receptor)
used for when you want hypotension during surgery, IV-administered, short acting.
o Primarily a receptor antagonist (so has affinity).
o BOTH drugs can however both antagonise and block nicotinic receptors.
Short acting
Describe the effect of GBDs on postural hypotension
In practice, the main effect is a marked fall in arterial blood pressure resulting mainly from block of sympathetic ganglia, which causes arteriolar vasodilatation, and the block of cardiovascular reflexes. Venoconstriction, which occurs normally when a subject stands up and prevents a fall in central venous pressure and cardiac output, is reduced. Standing thus causes a sudden fall in arterial pressure (postural hypotension) that can cause fainting.
Describe the effect of GBDs on postexcercise hypotension
The vasodilatation of skeletal muscle that occurs during exercise is normally accompanied by vasoconstriction elsewhere (e.g. splanchnic area) produced by sympathetic activity. Ganglion blockers prevent this adjustment, so the overall peripheral resistance falls leading to postexercise hypotension.
What do lots of venoms and toxins target
nAChrS
Issue is with somatic nervous system- venoms and toxins are designed to target these
Target diaphragm
Can’t move or breath- paralyses prey
